The invention is related to the area of radioconjugation technology. In particular it is related to the use of internalizing antibodies in radioimmunotherapy.
Monoclonal antibodies (mAbs) are attractive vehicles for targeting radiation to tumors because of their ability to react specifically with molecular determinants on cancer cells. However; the anticipated impact of labeled mAbs on the clinical management of cancer has yet to be achieved; loss of label from the mAb in vivo and uptake of radioactivity in normal tissues have impeded their clinical application. Iodine-131 is the most frequently used nuclide in clinical radioimmunotherapy, but its usefulness has been compromised by in vivo dehalogenation of mAbs labeled via conventional procedures.
Radiolabeled mAbs could play an important role in the diagnosis and treatment of cancer if the molecular specificity inherent in the mAb-antigen interaction can be successfully exploited to selectively deliver radionuclides to tumors. For many types of cancer, radioimmunotherapy is an attractive alternative to external beam radiation therapy and systemically administered chemotherapy, treatments that are frequently ineffective because of dose-limiting toxicities to normal tissues. Radioimmunoscintigraphy is appealing not only for lesion detection but also as a means for determining which patients are suitable candidates for labeled mAb therapy. Numerous clinical studies have confirmed the ability of labeled mAbs to localize in both primary and metastatic cancers (reviewed in Britton and Granowska, 1996; Larson, 1995), and in patients with radiosensitive tumors, significant therapeutic responses have been obtained with 131I-labeled mAbs (Press et al., 1995; Kaminski et al., 1996). However, other tumors have proven to be less radiosensitive, presumably due to the low level of radionuclide retained in tumor and the significant accumulation of radioactivity in normal organs (Kairemo, 1996; Bast et al., 1997). There remains a need in the art for improved techniques and reagents to selectively target both therapeutic and diagnostic radiolabels to tumor cells.
It is an object of the invention to provide radioconjugated ligands and methods of their use in locating and treating tumors. These and other objects of the invention are provided by one or more of the embodiments described below.
One embodiment of the invention provides a composition for internally labeling a cell. The composition comprising a ligand, an oligopeptide, and a label. The ligand is any moiety that specifically binds to a cell surface antigen or receptor and is internalized by the cell. The ligand is selected from the group consisting of an antibody, a fragment of an antibody, and a synthetic polypeptide. The oligopeptide comprises at least one positively charged amino acid residue and at least one D-amino acid residue. The oligopeptide does not comprise two or more contiguous L-amino acid residues. The oligopeptide is covalently bound to the ligand. The label is covalently bound to the oligopeptide.
Another embodiment of the invention provides a method of incorporating a label into a cell. The method comprises the step of contacting the cell with the composition described in the previous paragraph, whereby the label is internalized by the cell.
Still another embodiment of the invention provides a method of locating tumor cells in a mammal. The method comprises the steps of introducing a diagnostically effective amount of the above composition into the body of a mammal which comprises tumor cells, scanning the body with a scintillation detector, and generating an image depicting the tumor cells in the body of the mammal.
Yet another embodiment of the invention provides a method of radiotherapy. The method comprises the step of introducing a therapeutically effective amount of the above composition into the body of a mammal comprising a tumor, whereby growth of the tumor is diminished.
A further embodiment of the invention provides a compound for labeling a ligand which binds to a cell surface antigen. The compound comprises a molecule of formula (I): 
The xe2x80x94NHxe2x80x94 group represents the amino end and the 
group represents the carboxyl end of the molecule. AA represents an amino acid and n is an integer having a value of at least 1 and at most about 10, 15, or 20. R1 is H or an amino protecting group and R2 is H or a carboxyl protecting group, with the proviso that R1xe2x95x90R2xe2x95x90H is an unsatisfied condition for this molecule. Either R1 or R2 is H. At least one amino acid residue is positively charged and at least one amino acid residue is a D-amino acid. The molecule does not comprise two or more contiguous L-amino acids. At least one amino acid is sufficient to be coupled to a label. The molecule is sufficient to be coupled to a ligand at only one of its amino end or its carboxyl end.
The invention thus provides the art with novel tools to introduce labeled ligands into a cell.